Identification of CNS-Penetrant Tryptophan 2,3-Dioxygenase Degrading Ligands

CNS 渗透色氨酸 2,3-双加氧酶降解配体的鉴定

基本信息

批准号：
10511398
负责人：
Ryan A Altman
金额：
$ 23.59万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511398
关键词：
Active Learning Active Sites Affinity Alzheimer&apos s Disease Amino Acids Basic Science Binding Binding Sites Biochemical Biological Assay Biology Brain Catabolism Cell model Cell physiology Central Nervous System Diseases Chemistry Clinical Research Clinical Trials Drug Industry Drug Kinetics Enzyme-Linked Immunosorbent Assay FDA approved Future Heme Human Huntington Disease Immunology In Vitro Institution Joints Knowledge Kynurenine Lead Ligands Link Machine Learning Malignant Neoplasms Measures Mental Depression Metabolism Nerve Degeneration Neurons New Agents Parkinson Disease Pathway interactions Peripheral Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Pilot Projects Property Prosthesis Proteins Resistance Series Signal Transduction Site Solid Solubility Tryptophan Tryptophanase Ubiquitin Ubiquitination Up-Regulation Ursidae Family Work anxiety-related behavior design drug development drug distribution in vitro Assay in vivo inhibitor innovation neurogenesis neuropsychiatric disorder novel preclinical trial protein degradation scaffold small molecule therapeutic development tool virtual

Active Learning Active Sites Affinity Alzheimer&apos s Disease Amino Acids Basic Science Binding Binding Sites Biochemical Biological Assay Biology Brain Catabolism Cell model Cell physiology Central Nervous System Diseases Chemistry Clinical Research Clinical Trials Drug Industry Drug Kinetics Enzyme-Linked Immunosorbent Assay FDA approved Future Heme Human Huntington Disease Immunology In Vitro Institution Joints Knowledge Kynurenine Lead Ligands Link Machine Learning Malignant Neoplasms Measures Mental Depression Metabolism Nerve Degeneration Neurons New Agents Parkinson Disease Pathway interactions Peripheral Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Pilot Projects Property Prosthesis Proteins Resistance Series Signal Transduction Site Solid Solubility Tryptophan Tryptophanase Ubiquitin Ubiquitination Up-Regulation Ursidae Family Work anxiety-related behavior design drug development drug distribution in vitro Assay in vivo inhibitor innovation neurogenesis neuropsychiatric disorder novel preclinical trial protein degradation scaffold small molecule therapeutic development tool virtual

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项目摘要

ABSTRACT Tryptophan 2,3-dioxygenase (TDO) is a key modulator of physiological neurogenesis and anxiety-related behavior. Misregulated neuronal TDO activity causes elevated levels of tryptophan-kynurenine pathway metabolites, which in turn, causes depression, brain degeneration, and neurodegenerative Alzheimer's, Parkinson's, and Huntington's diseases. However, a critical need remains for identifying new agents that function through innovative mechanisms to probe a range of pharmacological hypotheses regarding central TDO action, ultimately advancing our overall pharmacological knowledge, and to also serve as leads for downstream medicinal chemistry optimization, thus helping people live long healthy lives. To identify innovative inhibitors, we engaged in a joint basic science-clinical study that identified a non-catalytic L-tryptophan (L-Trp) binding site in human TDO that binds L-Trp surprisingly much tighter than the catalytic heme site. The newly discovered L-Trp binding site is involved in regulating TDO activity and stability by suppressing ubiquitin-dependent degradation when loaded with L-Trp. This finding has inspired us to propose a central hypothesis that this newly discovered signaling site is an Achilles' heel of TDO for drug development. This application will fill the critical need to identify CNS-penetrant protein-degrading ligands for exploring their biomedical potential. Towards this end, we will employ our rigorous understanding of the underlying chemistry and biology to design compounds with a novel mode of action that destabilize the signaling site of TDO or bind without enhancing the protein stability. These agents will not target the catalytic activity of TDO but instead will disrupt its degradation resistance signal. We will assess the effects of promising compounds on human TDO in cellular models to validate the innovative approach and target. In the end, this work will open the door for designing revolutionarily new centrally-active inhibitors targeting human TDO.

抽象的色氨酸2,3-二氧酶（TDO）是生理神经发生和焦虑有关的关键调节剂行为。神经元TDO活性误导会导致色氨酸 - 酮氨酸途径的水平升高代谢物又导致抑郁症，脑退化和神经退行性阿尔茨海默氏症帕金森氏症和亨廷顿的疾病。但是，仍然需要确定功能的新代理的关键需求通过创新的机制来探究有关中央TDO作用的一系列药理假设，最终促进我们的整体药理学知识，并作为下游的潜在客户药物化学优化，从而帮助人们过着健康的生活。为了识别创新的抑制剂，我们参与了一项联合基础科学临床研究，该研究确定了非催化L- tryptophan（L-TRP）结合位点与催化性血红素部位相比，L-TRP结合的人类TDO的结合得多。新发现的L-TRP 结合位点通过抑制泛素依赖性降解来调节TDO活性和稳定性加载L-TRP时。这一发现激发了我们提出一个新发现的中心假设信号位点是用于药物开发的TDO的致命弱点。此应用程序将满足确定的关键需求中枢神经系统渗透蛋白降解配体用于探索其生物医学潜力。为此，我们将利用我们对基本化学和生物学的严格理解来设计化合物在不增强蛋白质稳定性的情况下破坏TDO或结合的信号传导位点的稳定的作用方式。这些代理不会针对TDO的催化活性，而是会破坏其降解信号。我们将评估有前途的化合物对细胞模型中人类TDO的影响以验证创新性方法和目标。最后，这项工作将为设计革命性的新中心活动打开大门针对人类TDO的抑制剂。